The long term objective of this research is to develop tissue engineering therapies for cartilage repair by understanding better the mechanisms of tissue repair and designing practical strategies that can be clinically applied. Tissue engineering is a multidisciplinary field that aims to regenerate and replace tissues lost due to disease, congenital abnormalities, or traumatic events. Orthopedic and plastic surgery are areas of medicine where tissue engineering has a potential to significantly improve surgical options by providing a source of tissue for repair and/or augmentation. Our strategy for repair involves a cell-laden hydrogel that can be injected in a defect and polymerized (solidified) in a minimally invasive manner using light. Mesenchymal stem cells photoencapsulated in a biomaterial scaffold will provide the basis for tissue repair. This proposal is both hypothesis and design driven. We hypothesize that degrading hydrogels will enhance tissue matrix production and will therefore investigate the synthesis of novel hydrogels with degradable phosphoester units. We also hypothesize that creating multilayered hydrogel structures will allow us to coculture cells in a 3D environment to 1.) engineer the zonal organization of cartilage, 2.) engineer osteochondral tissues, and 3.) investigate the influence of cell interactions (coculture) on tissue development. The design driven portion of the proposal will develop a clinically practical strategy for cartilage repair. The repair strategy will address 1.) biomaterial integration to the surrounding tissue and 2.) engineering new cartilage repair in an injectable hydrogel. The integration strategy will comprise a primer based on the biopolymer, chondroitin sulfate, modified with chemistries to provide a covalent bridge between cartilage and the injected hydrogel biomaterial. The envisioned tissue repair materials can be injected into a defect and photopolymerized in a minimally invasive fashion. To test these hypotheses and design the repair system the following specific aims will be investigated: Specific aim 1. Development of a novel biodegradable phosphoester-PEG photopolymerizing polymer for engineering cartilage and bone using adult bone marrow-derived mesenchymal stem cells. Specific aim 2. Engineering of multilayered hydrogels for development of zonally organized cartilage and osteochondral tissues. Specific aim 3. Chemical attachment of hydrogels to cartilage for improved tissue-implant integration in the joint.